The goal of this proposal is to better understand the intimate relationship between Borrelia burgdorferi, the Lyme disease agent, and one of its major tick vectors, Ixodes scapularis -- in order to develop novel strategies to prevent infection. We postulate that B. burgdorferi use tick salivary proteins (Salps) to facilitate infection of the mammalian host -- and this model is supported by our publication (Nature 436: 573-77, 2005) showing that spirochetes bind I. scapularis Salp15 during transmission from ticks, and that B. burgdorferi then use Salp15 to facilitate infection of mice. We now hypothesize that tick Salps that interact with B. burgdorferi may serve as targets for vaccines to prevent Lyme disease. We will develop this paradigm using, but not limited to, Salp15 as a model tick antigen. First, we will explore how B. burgdorferi use Salp15 to facilitate infection of the mammalian host. Second, we will determine whether B. burgdorferi rely solely on Salp15 to enhance infection of mice, or if the spirochetes also bind to, and use, additional tick Salps during transmission. Indeed, our preliminary data suggests that spirochetes adhere to several proteins in tick saliva. Third, and most importantly, we will determine whether immunization with a tick Salp - again using Salp15 as the first model antigen - can serve as a vaccine to prevent Lyme disease. We hope to show that arthropod proteins - critical for microbial survival in the mammalian host - can serve as targets for a pathogen-specific vaccine. If successful, these data may lead to new strategies for the prevention of B. burgdorferi infection, and this paradigm would also be applicable to other vector-borne pathogens of medical importance. PUBLIC HEALTH RELEVANCE: Lyme disease is the most common tick-borne illness in the United States. The causative agent is Borrelia burgdorferi, a spirochete. The goal of this proposal is to develop a better appreciation of the intimate relationship between Borrelia burgdorferi and its tick vector, Ixodes scapularis. The Lyme disease agent binds to several tick proteins during its transmission from ticks to mice or humans. By understanding these spirochete-tick interactions in greater detail, we will develop new ways to interfere with transmission of the Lyme disease agent. We hope to show that tick proteins - essential for B. burgdorferi survival in the mammalian host - can serve as targets for a Lyme disease vaccine. If successful, these studies may lead to new strategies for the prevention of B. burgdorferi infection. This paradigm would also be applicable to other vector-borne pathogens of medical importance.